Previous studies have shown that gamma delta T cells are over represented in the peripheral blood and broncheoalveolar lavages of humans infected with such viruses as human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). Similarly, in the mouse, intranasal infection with influenza or Sendai viruses induces the acculation of gamma delta T cells in the lung. Results reported herein show that coculture of human peripheral blood mononucler cells (PBMC) from herpes simplex virus (HSV)-immune individuals with HSV-infected PHA blasts results in the proliferation and expansion of gamma delta T cells expressing TCR variable (V) genes Vgamma2 paired with Vdelta2. These expanded Vgamma2Vdelta2 T cells lyse cells infected with HSV or with an unrelated virus, vaccxinia virus, but do not lyse mock-infected cells. This lysis is MHC-unrestricted and blocked by antibodies to the TCR. It thus appears that the process of acute viral infection induces or modifies a cell surface structure which is then capable of being recognized by gamma delta T cells. The available data suggest an antiviral role for gamma delta T cells. These studies propose to: 1) characterize the antigen and antigen presenting molecule recognized by virus-reactive Vgamma2Vdelta2 T cells; 2) determine by gamma delta TCR gene transfection if recognition of virus-infected cells is TCR-mediated; 3) characterize the virus-cell interactions which regulate cell surface expression of the antigen. These studies will help to determine the specificity of virus-reactive gamma delta T cells thereby enhancing understanding of their immunobiology and clarifying their role in antiviral immunity.